Rational Development of a Novel Attenuated Rift Valley Fever Virus Vaccine

新型裂谷热病毒减毒疫苗的合理研制

基本信息

批准号：
9386475
负责人：
Shinji Makino
金额：
$ 23.25万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-25 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386475
关键词：
Affect Africa Africa South of the Sahara Age Agriculture Animals Antigens Arthralgia Attenuated Attenuated Vaccines Bioterrorism Bunyaviridae Categories Cattle Cells Cellular Membrane Centers for Disease Control and Prevention (U.S.)Cessation of life Codon Nucleotides Country Culicidae Cultured Cells Data Development Disease Disease Outbreaks Economics Encephalitis Endemic Diseases Epidemic Epitopes Exhibits Family Fever Fluorouracil General Population Genetic Genome Genus Phlebovirus Glycoproteins Headache Health Status Human Humoral Immunities Immune response Immunity Immunization Immunize Immunocompromised Host Impairment Individual Invaded Literature Livestock Mass Vaccinations Mediating Movement Mus Mutation Myalgia National Institute of Allergy and Infectious Disease Neuraxis Neurologic Signs North America Orthobunyavirus Panic Patients Peptides Photophobia Play Population Production Property Proteins Public Health RNA Research Retinal Retinal Vasculitis Rift Valley fever virus Role Ruminants SCID Mice Safety Serial Passage Serological Sheep Testing Time Vaccination Vaccines Viral Viral Envelope Proteins Viral Hemorrhagic Fevers Viral Physiology Viral Structural Proteins Virion Virus Virus Diseases Virus Replication Virus-like particle Visual impairment Wild Animals base design economic impact genomic RNA immunogenic immunogenicity improved intraperitoneal macula member mouse model mutant neurovirulence neutralizing antibody novel pathogen prevent programs protective efficacy safety testing vaccine candidate vector viral transmission virus envelope

项目摘要

Abstract Rift Valley fever virus (RVFV), a prototypical Phlebovirus (family Bunyaviridae), belongs to the NIAID Category A list of pathogens and the CDC list of potential bioterrorism agents. RVFV causes a disease that is endemic in sub-Saharan Africa and can emerge in explosive, mosquito-borne epidemics decimating herds of sheep and cattle, resulting in enormous economic losses. In humans, RVFV infection may cause hemorrhagic fever, encephalitis, and retinal vasculitis. Many different mosquitoes, including several native to North America, are competent vectors for RVFV transmission. Thus, the introduction of RVFV into North America would likely cause panic in the general population, and the effects on livestock could have a devastating economic impact. Induction of a humoral immune response against the viral envelope proteins is necessary and sufficient to provide protection against RVFV. Currently, there is no RVFV vaccine suitable for mass human vaccination programs. The MP-12 strain, which was obtained by 12 serial passages of the wild-type RVFV strain ZH548 in the presence of 5-fluorouracil, is markedly attenuated in mice but retains its immunogenicity. However, intraperitoneal inoculation of MP-12 into young mice or SCID mice results in efficient virus replication in the animals’ central nervous system. The neuroinvasiveness and neurovirulence potential of MP-12 is a matter of concern when considering the mass vaccination of the general public, especially, in immunocompromised individuals. The present application proposes the development of a novel and safer MP-12-derived vaccine candidate having several mutations that selectively abolish specific functions of viral envelope glycoproteins and cause a higher expression level of neutralizing epitopes in infected cells. We will test the hypothesis that this MP-12-based vaccine candidate exhibits a better safety profile than MP-12 in mice but still retains its immunogenicity and protective efficacy. In this proposal, we will examine its genetic stability in cultured cells and assess its safety, immunogenicity, and protective efficacy by using mouse models.

抽象的 Rift Valley Fever病毒（RVFV）是一种典型的phlebovirus（Bunyaviridae），属于 NIAID类别的病原体清单和潜在生物恐怖剂的CDC清单。 RVFV 引起撒哈拉以南非洲内在的疾病，可以在爆炸性中出现，蚊子传播的流行病摧毁了绵羊和牛的牛群，导致了巨大的经济损失。在人类中，RVFV感染可能会导致出血热，脑炎和视网膜血管炎。许多不同的蚊子，包括北美本地的几个，是 RVFV传输的合格向量。那，将RVFV引入北美可能会引起普通人群的恐慌，对牲畜的影响可能具有毁灭性的经济影响。诱导对病毒的体液免疫反应信封蛋白是必要的，足以提供防止RVFV的保护。现在，没有适合大规模人类疫苗计划的RVFV疫苗。 MP-12菌株，这是通过在存在下的野生型RVFV菌株ZH548的12个串行通行证获得的 5-氟尿嘧啶在小鼠中显着减弱，但保留其免疫原性。然而， MP-12在年轻小鼠或SCID小鼠中接种MP-12会导致有效的病毒动物中枢神经系统中的复制。神经性创伤性和神经病毒病毒在考虑一般疫苗接种时，MP-12的潜力是一个问题公众，尤其是在免疫功能低下的个人中。当前的申请提案开发具有多个突变的新颖，更安全的MP-12衍生的疫苗候选者有选择地废除病毒包膜糖蛋白的特定功能，并导致更高被感染细胞中和表位的表达水平。我们将检验以下假设基于MP-12的基于MP-12的疫苗候选者比小鼠的MP-12表现出更好的安全性，但仍然保留其免疫原性和受保护的有效性。在此提案中，我们将检查其遗传学培养细胞中的稳定性并通过使用来评估其安全性，免疫原性和保护效率鼠标模型。